212138 A6 B6 經濟部中央標準局印裝 五、發明説明（1 ) 本發明傜關於2’，3’_二去氣嘌昤核苷治療逆轉每病毒 感染，包括人免疫缺乏病毒（H1V)感染在内。亦開於嗦 昤核苷代謝途徑抑制劑，尤其是嘌昤核苷磷酸化酶（PNP) 抑制劑。 本發明包含共同投予PNP抑制劑以及一種抗HI V活性二 去氣瞟昤核苷以治療HI V感染。 先天性免疫缺乏症候群（AIDS)為致命性疾病其持撳為 —条列免疫障礙，其傜於感染人免疫缺乏病毒（HlV)(De Clercq,路用化學期刊，Μ, 1561 (1986))之後而發展 出者ρ若干種治療AIDS之策略目前正在研究中（Mitsuya 及Broder,自然773 (1987))。今日，最為成功之 化學療法涉及2’，3’-二去氣核苷。此等葯劑産生5·-三 磷酸2’，3·-二去氣核苷酸（ddNT)類似物，此類似物藉着 呈抑制劑或呈基質類似物以為逆轉綠酶之功能依次阻止 HI V DNA合成及丨丨IV複製。於後例中，逆轉錄酶催化將 ddNT加成至生長中DNA鏈之3’端，由於缺少3’-羥基因而 終止進一步的延長。 已證實3’-疊氮基- 3’-去氣胸腺核苷（AZT)及二去氧胞 核苷（ddC)二者於人體治療HIV感染是有效的，及此二者 2’，3’-二去氣嘧啶核苷類似物經報告會延長葚命。然而 二者會産生一些磋重毒性副作用。AZT>會導致骨發抑制 及經常性剷烈貧血而ddC會導致末梢性神經病[Yarchoan 等人·， Lancet, 76 (1988)]。 (請先閱讀背面之注意事項再填寫本页) .装· 訂. •竦_ 甲 4(210X297 公爱) -3- A6 B6 經濟部中央標準局印裝212138 A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (1) The present invention is about the treatment of 2 ', 3'_degassed puroside nucleosides to reverse every viral infection, including human immunodeficiency virus (H1V) Inside. It is also open to inhibitors of the nucleoside metabolic pathway, especially purine nucleoside phosphorylase (PNP) inhibitors. The present invention includes co-administration of a PNP inhibitor and an anti-HI V activity dideoxyribonucleoside to treat HIV infection. Congenital Immunodeficiency Syndrome (AIDS) is a fatal disease and its persistence is-a series of immune disorders, which is after infection with human immunodeficiency virus (HlV) (De Clercq, Journal of Road Chemistry, Μ, 1561 (1986)) Several strategies for treating AIDS have been developed (Mitsuya and Broder, Nature 773 (1987)). Today, the most successful chemotherapy involves 2 ', 3'-dideoxynucleoside. These agents produce 5'-triphosphate 2 ', 3 · -degassed nucleotide (ddNT) analogues, which in turn act as inhibitors or matrix analogues in order to reverse the function of green enzymes in order to prevent HIV DNA synthesis and IV replication. In the latter example, reverse transcriptase catalyzes the addition of ddNT to the 3 'end of the growing DNA strand, and the further extension is terminated due to the lack of the 3'-hydroxyl group. It has been proved that both 3'-azido-3'-deoxythymidine (AZT) and dideoxycytidine (ddC) are effective in the treatment of HIV infection in humans, and the 2 ', 3' -Digasmidine analogs have been reported to prolong life. However, the two will produce some serious side effects. AZT > will lead to bone suppression and frequent anemia and ddC will cause peripheral neuropathy [Yarchoan et al., Lancet, 76 (1988)]. (Please read the precautions on the back before filling in this page). Packing and ordering. 竦 _ A 4 (210X297 public love) -3- A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs
2m38— 五、發明説明（2 ) 與六21'及£1(](：作比較，2’，3’-二去氣嗉昤核苷，例如二 去氣肌核苷（ddl)及二去氣腺核苷（ddA)於細胞培養中表 示出更有展望的治療指數（Mitsuya及Broder, Prol, Natl. Acad· Sci. δ3, 1911 (1986))。然而 ddl 舆 ddA 於保護H9細胞免於HIV傳染及ATH8細胞免於HIV细胞病變 方面較不具效力。此效力降低的一悃原因可能是代謝不 穩定所致。培育嘌昤琛中帶有絰ddl或ddA放射標檄過之 所有細胞，發現産生疑似抗-HIV剤2’，3’-二去氣腺核苷 -5’ -三磷酸（ddATP)及標楼ATP與ADP之實質數置。ddATP 假定是由ddl (活鑲内ddA邊速轉換為ddl)轉換為ddIHP (2’，3’-二去氧肌核苷單磷酸 > 隨後藉腺嗦昤基琥珀酸 合成酶（Ahluwalia等人，生物化學gf劑36, 3787 (1987))再進入腺嘌昤基鹽.途徑。而另一方面，經標楢 · ........ 之ATP及ADP則藉嗦昤核苷搽酸化梅（PNP)於ddl開始降解 為2’，3’-二去氣核糖-1’-磷酸鹽（(^1^)及次黃嗦昤（}1)0 時出現。經標幟之次黃嗉昤随後經由曛昤救援途徑 (Haertle等人·，生物化學期刊红立，5870 (1988)) 轉換為腺嘌昤基核苷酸。已知ddl為PNP基質，但與天然 PNP基質，肌核苷與鳥核苷柑比較，ddl實質上較差 (1000X 較低 kcat/kn; Stoeckler 等人•，生物化學 ϋ, 102 (1980))。因此，由此種相當差的PNP基質於細胞培 養中藉PNP可大幅降解的事實推斷若非PNP於此等淋巴球 細胞条中大量存在，則傜或/及ddl經璘酸化而成ddIMP (請先閏讀背面之注意事項再瑱寫本頁) •装· •訂· •緣·· 甲 4(210X297 公爱） A6 B6 212138 五、發明説明（3 ) 之反應相當缓慢。 與細胞培養作比較，於所有動物中PNP對ddl人體葯力 學之影铤一無所知。清楚的是，活體内ddl排除作用可 藉許多不同機制包括资臓過濾作用，氣化作用，结合作 用，化學水解作用等産生。由單一葫催化葯劑之降解作 用及藉此測得葯劑於活體内之半衰期，葯劑必定已經接 融到酶且其轉換率必定較所有其它已知機制之速率明顯 地快許多。由ddl為一種非常差的PNP基質之事實，因而 易於推斷活髏内ddl排除之速率不可能块定在PNP的活性 ，因此不可能受到PNP抑制劑的影逛。 於本技g界中已知有棰多樣化之螵昤核苷磷酸化酶 (PNP)抑制劑。許多此等抑制劑特別掲示於癌症化學療 法之發展性中J· Stoeckler之章節内，CRC出版，1984 年，篇名 '"瞟昤核苷菘酸化酶：化學療法之目標# ,第 35-60頁及於未來之葯品第3號，1988年，*嗦呤核 苷磷酸化酶（PNP)抑制劑：增強選擇性免疫抑制劑"， Sircar與Gilbertsen,第 653- 668頁；EP-A-193,454, EP-A-178,178, EP-A-156,559, EP-A-145,207 及 EP-A-260,491〇 發現PNP缺乏或抑制會壓抑Τ細胞協調性免疫，如同上 述文章所提出者；而且可見於癌症研究1986年2月. "藉嗦聆核苷磷酸化_，8-胺基-芣基鳥嘌昤之新穎抑制 性而增強2’-去氣鳥嘌昤核苷细胞毐性"，第519-523頁 {請先閱讀背面之注意事項再瑱寫本頁) •装， •訂· .線· 甲 4(210X297 公嬗） -5- A6 B6 iHMSS— 五、發明説明（4 ) ;癌症研究jj, 1774 -1778, 1986年4月；葯劑與反應ϋ, 3/4 (1987),第 253-256 頁；葯劑與反應 21, 3/4 (1987), 第 379-384頁；葯劑與反應ai, 3/4 (1987),第 272-274 頁；免疫學1986, §1,第63 - 67頁；及臨床實驗免疫學 (1986), M,第166-172頁。此等文獻澄清PNP缺乏會導 致T細胞死亡且危害寄主免疫整合性。細胞缺乏PNP會累 積嘌昤核苷磷酸三磷酸而使细-胞死亡。事實上，Τ细胞似 乎為因ΡΝΡ缺乏毒性而最受影堪之細胞。因於免疫者ΡΝΡ 活性降低會危害患者，例如AIDS患者將出現禁忌徴候。 因此投予PNP抑制劑似乎為禁忌戡候以作為克服逆轉貧 病毒，尤其為人免疫缺乏病毒感染之方法。PNP抑制劑 對此種感染預期會進一步危害免疫功能。 雖然如上所言，當今發明傜直接投予2’，3’-二去氣嗦 昤核苷（或其衍生物）合併嘌昤核苷璘酸化酶抑制劑而 因此抑制代謝降解作用及促進該2’，3’-二去氣嗦昤核苷 (或其衍生物）以治療人免疫缺乏病毒（HIV)感染。 本發明之一目的係提供治療逆行病毒感染，尤其是人 免疫缺乏病毒感染，及其組成物之方法。 本發明之另一目的傜提供一種2’，3’-二去氣嗦昤核苷 治療人免疫缺乏病毒感染及於哺乳動物，包括人在内之 其它2’，3’-二去氣嘌昤核苷反應條件之改良方法。 本發明之又另一目的你提供一種於哺乳動物，包括人 • 在内之減M2’，3’-二去氣嗉昤核苷在活體内之代謝或降 {請先閲讀背面<-注意事V再填寫本页) •裝. .訂· .線. 經濟部中央標準局印裂 甲 4(210X297 公爱） 一 6— 212138 A6 B6 五、發明説明（5 ) 經濟部中央標準局印裝 代謝酯或葯學可接受性鹽。式I化合物之酯類係式I化 合物中氩氧甲基中之羥基以酸酯化，包括a)式R* -COOH 酸之羧酸酯，其中係菜自直式及分支式烷基，烷氣烷 基，芳基烷基，芳氣烷基及芳基，其中芳基為苯基或禁基 未取代或經取代鹵素，烷基或烷氣基者；b)式h -SO, Η 磺酸之磺酸酯，其中為烷基或芳基烷基，芳基被定 義如上；c)下式磷酸之磷酸酯· r3〇 \ R4O一 P =0 r5〇/ 式中R3 -Rs至少有一崔非為氫，R, -Rs换菝自氫及 如上R»所表示之群基。上述中，烷基及烷氣基各自有1 -18,較好為1-7,更好為1-4傾硪原子。鹵素代表較好 為氟或氛。嗦昤鹺基团B代表較好為腺嗦昤-9-基，鳥 糞嘌昤-9-基，次黃嫖昤-9-基，硫基次黃瞟昤-9-基，昧基鳥糞螵昤-9-基或2-胺基腺嘌昤-9-基》 較好為式I之對應化合物其中A代表氢，Β為腺嘌昤-9-基，鳥糞瞟昤-9-基，次黃嗦昤-9-基，硫基次黃嘌 昤-9 -基，硫基烏糞嗦昤-9-基或2-胺基腺嗦昤-9-基； 及不具氩氣基，主要為2’，3’-二去氧腺核苷，2’，3^ 二去氣鳥糞噤昤核苷，2’，3·-二去氣肌核苷，2’，3’-二去氧硫基肌核苷，2\3’·二去氣硫基鳥糞嗦昤核苷及 2’，3’-二去氣-2-胺基腺核苷。尤其較好者為對應化合 -請 先 閲 讀 背 面 之. 注 意1- 再 瑱 寫 本 页 裝 訂 缘 甲 4(210X297;鐘） 212138 五、發明説明（6 ) A6 B6 解之方法，一種増加反應期間之方法，一種增強療放之 方法，一種減少有效劑量之方法，及一種以該2’，3’-二 去氣嘌昤核苷治療時減少所觀察到副作用之方法。 本發明之進一目的係提供一種组成物，以次療法董治 療於哺乳動物，包括人在内之2Λ ,3’-二去氧嗦昤核苷反 應性病情。 令人驚訝的是，此等及其它目的僳藉投予患有2’,3’- 二去氣瞟昤核苷反應性病情之哺乳動物2’，3’-二去氣嗦 . . 昤核苷及嘌昤核苷酸化酶抑制劑二者而完成。 本發明為一種合併療法及治療逆轉錄病毒感染，待別 於人，尤其是人免疫缺乏病毒感染之组成物。它必須投 予2’，3^二去氣嘌昤核苷（ddPN)及嗦昤核苷磷酸化梅抑 制剤（PNP抑制劑）及時將之充分封閉，如此PNP抑制将阻 止，或至少降低，藉天然嗦昤核苷酸化成對2、3’-二去 氣嘌昤核苷所産生之代謝速率。 本發明使用之2’，3’-二去氣暖昤核苷僳例如式（I )化 合物2m38— V. Description of the invention (2) Compared with Liu 21 'and £ 1 () (: for comparison, 2', 3'-didegastropine nucleosides, such as dideoxyinosine (ddl) and digoline Air nucleoside (ddA) shows a more promising therapeutic index in cell culture (Mitsuya and Broder, Prol, Natl. Acad · Sci. Δ3, 1911 (1986)). However, ddl and ddA protect H9 cells from HIV infection and ATH8 cells are less effective in avoiding HIV cytopathy. One reason for this decrease in efficacy may be due to metabolic instability. Cultivate all cells with purplish ddl or ddA radioactive standards in purulium and found Produced suspected anti-HIV 2 ', 3'-di-deoxyadenosine-5'-triphosphate (ddATP) and the actual number of standard buildings ATP and ADP. DdATP is assumed to be derived from ddl (live ddA side speed Converted to ddl) Converted to ddIHP (2 ', 3'-dideoxyinosine monophosphate > subsequently borrowed from glandular succinate synthetase (Ahluwalia et al., Biochemical Gf Agent 36, 3787 (1987)) Re-enter the adenine salt. Pathway. On the other hand, the ATP and ADP of the standard ........................ 2 ', 3'-Didegas ribose-1'-phosphate ((^ 1 ^) and hypo-yellowishness (} 1) appear at 0. The flagged hypo-yellowlyness followed by the rescue route (Haertle et al., Journal of Biochemistry Hongli, 5870 (1988)) Converted to adenine nucleotide. Ddl is known to be a PNP matrix, but compared with the natural PNP matrix, myosin and guanosine, ddl is substantially poorer (1000cat lower kcat / kn; Stoeckler et al., Biochemistry ϋ, 102 (1980)). Therefore, it is inferred from the fact that this rather poor PNP matrix can be greatly degraded by PNP in cell culture. PNP exists in a large amount in these lymphocyte cell strips, then dvd or / and ddl are acidified to form ddIMP (please read the precautions on the back before writing this page) • Install · • Order · • Edge · · A 4 (210X297 public love) A6 B6 212138 V. Description of the invention (3) The response is quite slow. Compared with cell culture, PNP has no knowledge of the ddl human pharmacodynamics in all animals. What is clear is that the living body The internal ddl exclusion effect can be borrowed from many different mechanisms including resource filtration, gasification, binding, chemical hydrolysis Produced by a single gourd catalyzing the degradation of an agent and measuring the half-life of the agent in vivo, the agent must have been fused to the enzyme and its conversion rate must be significantly faster than the rate of all other known mechanisms. The fact that ddl is a very poor PNP matrix makes it easy to deduce that the rate of ddl elimination in living skulls cannot be determined by the activity of PNP and therefore cannot be influenced by PNP inhibitors. In the art, there are known a wide variety of inhibitors of nucleoside phosphorylase (PNP). Many of these inhibitors are particularly shown in the chapter of J. Stoeckler in the Development of Cancer Chemotherapy, published by CRC, 1984, titled "" 枟 护 护 溤 銀 菘 菘 菀 鐵: The goal of chemotherapy #, 第 35- 60 pages and future medicine No. 3, 1988, * Pyrrhodoside nucleoside phosphorylase (PNP) inhibitors: enhanced selective immunosuppressants ", Sircar and Gilbertsen, pages 653-668; EP-A -193,454, EP-A-178,178, EP-A-156,559, EP-A-145,207 and EP-A-260,491. PNP deficiency or inhibition found to suppress T cell coordinated immunity, as proposed in the above article; and can be found at Cancer Research February 1986. " Enhancement of 2′-degassed guanosine nucleoside cell enhancement by novel inhibitory effect of nucleoside phosphorylation of _, 8-amino-fluorenyl guanosine ", Pages 519-523 (Please read the precautions on the back before writing this page) • Install, • Order ·. Line · A 4 (210X297 public transmutation) -5- A6 B6 iHMSS— V. Invention description (4); Cancer Research jj, 1774 -1778, April 1986; Drugs and Reactions ϋ, 3/4 (1987), pages 253-256; Drugs and Reactions 21, 3/4 (1987), pages 379-384 Pharmacy and reaction ai, 3/4 (1987), pp. 272-274; Immunology 1986, §1, first 63--67 page; experimental and clinical immunology (1986), M, pp. 166-172. These documents clarify that PNP deficiency can cause T cell death and compromise host immune integration. Cells lacking PNP will accumulate puronucleotide triphosphate and cause cell death. In fact, T cells seem to be the most affected cells due to PNP's lack of toxicity. Because the decreased PNPP activity of the immunized person will harm the patient, for example, AIDS patients will have contraindications. Therefore, the administration of PNP inhibitors seems to be a contraindication to overcome the reversal of poor virus, especially for human immunodeficiency virus infection. PNP inhibitors are expected to further compromise immune function against such infections. Although as mentioned above, the present invention is directly administered to 2 ', 3'-didegastropine nucleoside (or its derivatives) combined with purine nucleoside phosphorylase inhibitors, thus inhibiting metabolic degradation and promoting the 2 ', 3'-Di-degassy nucleoside (or its derivatives) to treat human immunodeficiency virus (HIV) infection. An object of the present invention is to provide a method for treating retroviral infections, especially human immunodeficiency virus infections, and compositions thereof. Another object of the present invention is to provide a 2 ', 3'-didegastropine nucleoside for the treatment of human immunodeficiency virus infection and other 2', 3'-didegastropine in humans, including humans Improved method of nucleoside reaction conditions. Another object of the present invention is to provide a reduction in M2 ', 3'-didegastropine nucleoside metabolism or reduction in mammals, including humans. {Please read the back <-Note Matter V and then fill out this page) • Installed. Ordered.. Line. The Central Bureau of Standards of the Ministry of Economic Affairs printed the split armor 4 (210X297 public love) one 6-212138 A6 B6 5. Description of invention (5) Printed by the Central Bureau of the Ministry of Economic Affairs Metabolic ester or pharmaceutically acceptable salt. The esters of the compound of formula I are the esterification of the hydroxyl group in the oxymethyl group of the compound of formula I, including a) the carboxylic acid ester of the formula R * -COOH acid, wherein the dishes are straight and branched alkyl, alkyl Gas alkyl, aryl alkyl, aryl gas alkyl and aryl, wherein aryl is phenyl or unsubstituted or substituted halogen, alkyl or alkyl gas; b) formula h -SO, Η sulfon Sulfonic acid ester of acid, which is alkyl or arylalkyl, aryl group is as defined above; c) Phosphate ester of phosphoric acid of the formula: r3〇 \ R4O-P = 0 r5〇 / where R3-Rs has at least one Cui Rather than hydrogen, R, -Rs are replaced by hydrogen and group groups as indicated by R »above. In the above, the alkyl group and the alkyl group each have 1-18, preferably 1-7, more preferably 1-4 atoms. Halogen represents preferably fluorine or atmosphere. Sudden wing group B represents preferably glandular -9-yl, guano purine-9-yl, hypoyellow lin-9-yl, sulfur-based hypoxanthine -9-yl, amyl guano "L-9-9-yl or 2-aminoadenine-9-yl" is preferably a corresponding compound of formula I where A represents hydrogen, B is adenine-9-yl, guano-9-yl, Hypoxanthin-9-yl, thio-hypoxanthine-9-yl, thioxanthene -9-9-yl or 2-aminoadenine-9-yl; and without argon, mainly 2 ', 3'-dideoxyadenosine nucleoside, 2', 3 ^ dideoxyguanosporine nucleoside, 2 ', 3 · -dideoxyinonucleoside, 2', 3'-dideoxythio Inosine, 2 \ 3 '· didegasthioguanosine nucleoside and 2', 3'-didegas-2-aminoadenosine. The better is the corresponding compound-please read the back first. Note 1- Then write this page to bind the edge armor 4 (210X297; Bell) 212138 5. Description of the invention (6) A6 B6 solution method, an increase during the reaction period Method, a method of enhancing radiotherapy, a method of reducing the effective dose, and a method of reducing the observed side effects during treatment with the 2 ', 3'-didegastropine. A further object of the present invention is to provide a composition for the treatment of 2Λ, 3'-dideoxydeoxyribonucleoside reactive diseases in mammals, including humans, by secondary therapy. Surprisingly, these and other purposes were administered to mammals suffering from 2 ', 3'-digodipine nucleoside-reactive conditions. Completed by both glycosides and purine nucleotidase inhibitors. The present invention is a combination therapy and treatment of retroviral infections, to be distinguished from humans, especially the composition of human immunodeficiency virus infections. It must be administered with 2 ', 3 ^ -degassed puroside nucleoside (ddPN) and syrup nucleoside phosphorylated plum inhibitor (PNP inhibitor) in a timely manner to fully block it, so that PNP inhibition will prevent, or at least reduce, The metabolic rate produced by natural nucleated nucleotides to form pairs of 2, 3'-didegas purine nucleosides. The 2 ', 3'-didegas warming nucleoside peptides used in the present invention are, for example, compounds of formula (I)
(請先閲讀背面、<-注意事項再填寫本頁) •裏. •訂. .線· 經濟部中央椋準局印製 式中A為氫.β氮基或鹵素，較好為氫，B代表嗦昤鹺基 以其第9位置結合二去氣糖殘基之基圃及式I化合物之可 甲 4(210X297 公簷） -8- A6212138_5! 五、發明説明（7 ) 經濟部中央標準局印裝 物中A為氫，B為腺嘌昤-9-基，鳥糞嗦昤-9-基，次黃 瞟昤-9-基或硫基次黃嘌昤-9 -基及不具氫氧基•主 要為2’，3’-二去氧腺核苷，2’，3·-二去氧鳥糞嘌昤核苷 ,2’，3’-二去氣肌核苷及2’，3’-二去氣硫基肌核苷。最 好者為對應化合物中A為氫，B為腺嗦昤-9-基或次黃嗦昤 -9 -基；及不具氫氧基者，主要為2\3’-二去氣腺核 苷及2’，3’,-二去氣肌核苷。 、上述化合物為已知或可依據於技苞界中普遍皆知之技 術，例如於£卩1_206,497, 1?1§^12月30日出販，製造。 式（I )化合物之葯學可接受性衍生物之特定實施例可 依據本發明包括下列V酯及葯學可接受性驗性金羼發， 較好為單鈉鹽：單磷酸鹽；二納單磷酸發；二砖酸鹽； 三磷酸鹽；乙酸鹽；3-甲基丁酸酯；辛酸酯；棕櫊酸酯 ;3-氛苯甲酸鹽；4-甲基苯甲酸鹽；氫琥珀酸鹽；三甲 基醋酸鹽，甲磺酸鹽。 ,例如式I二去氧嗦昤核苷之抗逆轉移病毒效力之增強 ，可藉PNP抑制剤決定，例如於细胞培養（例如H9細胞， ATH8細胞）根據技蓊界中廣為人知之方法論，例如Pr〇L Nat· Acad· Sci.美國 Μ, 1911 (1986)所述者曝露逆 轉錄病毒（例如HIV)。此增強性亦可於活體内（例如： 大鼠）藉測定二去氣嗦昤核苷於血漿層之增加而決定， 該項測定你根據技薛界中已知之方法論以先前或冏時投 予特殊PNP抑制劑而完成。 {請先閲讀背面之注意事項再填寫本頁) •襄· -訂· •線. 甲 4(210X297 公簷） -9- ^12138 A6 B6 經濟部中央標準局印裂 五、發明説明（8 ) 根據本發明，化合物可藉任何適宜途徑包括口，直腸 ，畀，局部（包括頰及舌下），陰道，非經腸道的（包 括皮下，肌内，靜脈内及皮内）及經皮之方式投予以治 療。較佳之途徑將依接受體之病情及年齡，感染之本性 及遘用之活性成分而具差異。 -般而言ddPN之適宜劑量為毎天接受體每公斤體重约 0.01至20呢之範圍内，較佳者為每天每kg雇重约0.05至 10B8之範圍内及最佳者為每天毎kg韁重約0,1至5呢之範 圍内。欲求劑量較好表示以2,3,4,5,6或更多小劑量於 一天中之適宜間隔投予。此等小劑量可以單位劑量型式 投予，例如含有大約0.1至200呢，較好約0,5至100呢， 及最好約1·0至5 0呢之活性成分毎單位劑量型式。 理想的是投予ddPN成分而使活性化合物達到頂點血漿 濃度由約1至75«M,較好約2至58«M,最好約3至30«M。 雖然單獨投予活性成分是可能的，惟較好以葯學配方 投予。本發明之配方包括至少一種活性成分，如此中定 義者，與一種或多種可接受性載劑及非必要地其它治療 劑。每餹載劑必須為'"可接受性的#，亦邸與處方之其 它成分相容及不危害患者。處方包括迪宜由口，直腸， 男，局部（包括頰及舌下），陰道，非經腸道（包括皮 下，肌内，靜脈内及皮内）或經皮投予者。此處方可便 利地以單位劑量型式表示及以葯劑技薛界已知之任何方 法製備。此等方法包括組合活性成分與載劑，該載劑偽 (請先閱讀背面<-注意事項再填寫本頁) .裝· •訂· 綵· 甲 4(210X297 公簷） 10_ A62121&8-^ 五、發明説明< 9 ) 經濟部中央標準局印製 由一種或多種附屬成分所组成。一般而言，處方傜以均 勻地组合活性成分與液體載劑或精巧地分割固體載劑或 以二者之方式製備，若有需要則將産品成型。 本發明適於口服之配方可以分離單位例如膠囊，廇囊 劑或錠毎個含有活性成分預先決定量；以辦末或顆粒； 以溶液或懸浮液於水溶性或非水溶性液鍰内；或以油在 水中之液體乳液或水於油中之'液體乳液之方式表示。活 性成分亦可以九粒，舐劑或糊劑之方式投予。 錠可以壓缩或成型方式裂造，非必要地與一或多種附 屬成分。壓縮式錠之裂造係將活性成分以不會流動型式 例如粉末或顆粒，非必要地與结合劑（例如Povidone, 明膠，氫氧丙基甲基纖維素），潤滑劑，惰性稀釋劑， 保存液，表面活性分解劑（例如澱粉乙酵酸鈉，交互聯 结povidone,交互聯結鈉羧基甲基鐵維素）或分散劑混 合，於適宜機器内歷缩。成型式錠偽將粉末狀化合物與 愤性液體稀釋劑潤徑之混合物於適宜機器中成型製成。 錠可非必要地塗覆或裂錠心及調K因而提供其中使用之 活性成分缓慢或控制性釋出，例如以不同比例之氢氣丙 基甲基餓維素以提供所箱之釋出閥。錠可菝擇性地外被 腸包衣，而於部分腸中非為胃中釋出。此點對式（1>化 合物尤其有利，因此種化合物對酸水解敏感。 適於口部局部投予之配方包括錠K含有具有香味，通 常為蔗糖及亞拉伯膠或西黃蓍膠之活性成分·•糖錠含有 請 先 閲 讀 背 之· 注 意 事· 項 再 瑱 窝 本 頁 裝 訂 線 f 4(210X297 公簷） -11- 經濟部中央標準局印裝 A6 --- 五、發明説明（1ϋ) 惰性基礎例如明膠及甘油，或蔗糖及亞拉伯膠之活性成 分；及漱口劑含有適宜液鳆載劑之活性成分。 由直腸投予之配方偽以含有如可可脂或柳酸鹽之適宜 鹽基之塞劑代表。 適於陰道投予之配方偽以子宮托，填塞劑，乳劑，凝 膠體，糊劑，泡沫或噴辖配方表示，其中除了 ddPN成分 外，含有例如技越界中已知之載劑是適切的。 適於以非經賭道投予之配方包括水溶性及非水溶性等 . · · . 張無菌注射液，該注射液含有抗氣化劑，缓衝劑，制菌 劑，及溶質，該溶質係以接受髏之血液溶解謂配之等張 液；及水溶性及非水溶性無菌憨浮液，該懸浮液含有懸 浮剤及稠厚劑。該配方可以單劑量或多剤量密封容器表 示，例如安瓿及小瓶，及可貯存於冷凍乾燥條件下，僅 須在使用前立卽加人無菌液體載劑，例如水以供注射用 。速成注射液及懸浮液可由前面所述之無薗粉末，顆粒 及錠等而製備。 較佳單位劑量配方係含有單日剤量或單位，單日小劑 量，或ddPN成分及/或PNP抑制劑之適宜部分。 本發明使用之嗉昤核苷链酸化酶（PNP)抑制劑係多樣 性化合物，其中JI：許多於技藉界中為典型已知者。許多 • - -- — —. — ______- 此等化合物特別掲示於癌症化學療法之發展性> Stoeckler之章節内，CRC出販，1984年，篇名★嘌昤 核苷磷酸化_ :化學療法之目標第35 - 60頁及於未 (請先閑讀背面之注意事項再填寫本頁) .裴· ，訂· •線， 甲 4 (210X297 公芨） -12- A6 B6 2^138- 五、發明説明（11) 來之葯品11,第7號，1988年Λ嗦昤核苷磷酸化酶（PNP) 抑制劑：增強選擇性免疫抑制劑〃，Sircar與Gilbertsen, 第653-668頁。亦參見美國專利申請案第704,991號，棠 编1985年2月25日，對應EP-A-193, 454 ;美國專利申諳 案第660, 152號，1984年10月12日棄编及美國專利申諳 案第767, 202號，1985年8月22日窠编，對應已卩4-178,178 ;美國專利申諳案第593, 063號，1984年3月26日_编及 美國專利申誚案第698, 905號，1985年2月11日彙编，對 應圧？4-156,559 ;美國專利申諳案第547, 297號，1983 年10月31日縈编及美國專利申諳案第657, 211號，1985 年6月19日彙编，對應EP-A-14 5, 207 ;及美國專利申諳案 第900,4 8 6號，1986年6月26日觉编及美國專利申謫案第 59,419 號，1987年 6 月 18 日彙编，對應 EP-A-260,491 ; 所有皆藉文獻於此併述。 此項掲示由許多PNP抑制劑所组成，本發明並非掻受 限制而可使用任何PNP抑制性化合物。 PNP抑制剤之PNP抑制性以具有1C »。小於5u者為 較佳。 本發明之一特殊具镰例傜两於使用2’，3·-二去氣嗦昤 核苷，例如2、3’_二去氧肌核苷或2’，3·-二去氣腺核苷 ，合併9-取代有鳥糞嘌昤之衍生物，例如掲示於EP-A-178,178(美國專利案第 4,772, 286號），EP-A-156,559 ，葯劑與反應3/4 (1987)第253 - 256頁及未來之葯 (請先閲讀背面t注意事項再瑱寫本頁) •裝· ’訂· 經濟部中央標準局印裝 甲 4(210X297 公爱） -13- 212138 A6 B6 五、發明説明（12) 劑 11, 653 (1988),或併合 EP-A-260,491 之 9-取代有 9-去吖鳥糞嘌昤之衍生物，例如下式(Please read the back, <Notes before filling in this page) • Inside. • Order .. Line · In the printed form of the Central Bureau of Economic Affairs of the Ministry of Economics, A is hydrogen. Β nitrogen or halogen, preferably hydrogen, B stands for the base garden with di-degassed sugar residues at its 9th position and Kejia 4 (210X297 common eaves) of the compound of formula I -8- A6212138_5! V. Invention description (7) Central Standard of the Ministry of Economic Affairs In the printed version, A is hydrogen, B is adenine-9-yl, guano-wax-9-yl, hypoxanthine-9-yl or thio-hypoxanthin-9-yl and does not have hydroxyl groups. • Main 2 ', 3'-dideoxyadenosine, 2', 3 · -dideoxyguanosine, 2 ', 3'-dideoxynucleoside and 2', 3'-di Degassed thioinosine. The best one is that in the corresponding compound, A is hydrogen, B is glandular-9-yl or hypoyellow-9-yl; and those without hydroxyl groups are mainly 2 \ 3'-dideoxyadenosine And 2 ', 3',-didebrosine. The above-mentioned compounds are known or can be based on techniques generally known in the technical field, for example, they are sold at £ 1_206,497, 1? 1§ ^ on December 30 and manufactured. Specific examples of pharmaceutically acceptable derivatives of compounds of formula (I) may include the following V esters and pharmacologically acceptable test results according to the present invention, preferably monosodium salts: monophosphate; dinamonophosphate Hair; dibromite; triphosphate; acetate; 3-methylbutyrate; octanoate; palmitate; 3-chlorobenzoate; 4-methylbenzoate; hydrogen succinate Acid salt; trimethyl acetate, mesylate. For example, the enhancement of the anti-retroviral efficacy of the dideoxynucleoside nucleoside of formula I can be determined by PNP inhibition, for example in cell culture (eg H9 cells, ATH8 cells) according to well-known methodologies in the technical field, such as Pr ○ L Nat · Acad · Sci. U.S. M, 1911 (1986) The person exposed to retroviruses (such as HIV). This enhancement can also be determined in vivo (for example: rats) by measuring the increase of the two degassed nucleosides in the plasma layer. In this measurement, you can administer the special PNP before or at the time according to the methodology known in the technical world. Inhibitors. {Please read the precautions on the back before filling out this page) • Xiang · -Order · • Line. A 4 (210X297 eaves) -9- ^ 12138 A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economy V. Description of invention (8) According to the present invention, the compound can be administered by any suitable route including oral, rectal, pancreatic, topical (including buccal and sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous and intradermal) and Treatment. The preferred route will vary depending on the recipient's condition and age, the nature of the infection and the active ingredients used. -Generally speaking, the appropriate dosage of ddPN is within the range of about 0.01 to 20 per kilogram of body weight per day, the preferred is within the range of about 0.05 to 10B8 per kg of daily weight and the best is per day per kg of rein It weighs about 0,1 to 5 in the range. Desirable doses indicate that small doses of 2, 3, 4, 5, 6 or more are administered at appropriate intervals throughout the day. These small doses can be administered in unit dosage forms, for example containing about 0.1 to 200, preferably about 0,5 to 100, and most preferably about 1.0 to 50, active ingredient per unit dosage form. It is desirable to administer the ddPN ingredient to bring the active compound to a peak plasma concentration of from about 1 to 75 «M, preferably from about 2 to 58« M, and most preferably from about 3 to 30 «M. Although it is possible to administer the active ingredient alone, it is better to administer it in a pharmaceutical formulation. The formulation of the present invention includes at least one active ingredient, as defined herein, with one or more acceptable carriers and optionally other therapeutic agents. Each carrier must be '" acceptable #, and Yidi is compatible with other ingredients of the prescription and does not harm the patient. Prescriptions include those administered by mouth, rectum, male, topical (including buccal and sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous and intradermal) or percutaneous administration. This prescription can be conveniently expressed in unit dosage form and prepared by any method known in the pharmaceutical art. These methods include the combination of the active ingredient and the carrier, which is false (please read the back < -precautions before filling in this page). Install · Order · Color · A 4 (210X297 public eaves) 10_ A62121 & 8- ^ V. Description of the Invention < 9) The printing issued by the Central Bureau of Standards of the Ministry of Economic Affairs consists of one or more subsidiary components. In general, the prescription is prepared by uniformly combining the active ingredient with the liquid carrier or delicately dividing the solid carrier or both, and molding the product if necessary. The formula suitable for oral administration of the present invention can be separated into units such as capsules, sachets, or tablets containing a predetermined amount of active ingredients; to be used as a powder or granules; as a solution or suspension in a water-soluble or water-insoluble liquid; or Expressed as a liquid emulsion of oil in water or a 'liquid emulsion of water in oil. The active ingredient can also be administered in the form of nine tablets, licks or pastes. The ingot can be cracked by compression or molding, optionally with one or more accessory ingredients. Compression of compressed ingots is to store the active ingredients in a non-flowing form such as powder or granules, optionally with binding agents (such as Povidone, gelatin, hydroxypropyl methylcellulose), lubricants, inert diluents, storage Liquid, surface active decomposer (such as sodium starch acetate, cross-linked povidone, cross-linked sodium carboxymethyl ferrovitamin) or dispersant mixed, shrink in a suitable machine. Molded ingots are made by molding a mixture of powdery compound and indignant liquid diluent in a suitable machine. The ingot can be coated or cracked unnecessarily and the K can be adjusted to provide slow or controlled release of the active ingredients used in it, for example, hydrogen propyl methyl carbaryl in different proportions to provide the release valve in the box . The tablets can be selectively coated with the intestines outside, but not released in the stomach in part of the intestines. This is especially advantageous for the compound of formula (1>, so this compound is sensitive to acid hydrolysis. Formulas suitable for topical oral administration include tablets K containing flavor, usually sucrose and gum arabic or tragacanth activity Ingredients •• Sugar tablet contains please read the back first. Note. Items and items on this page. Binding line f 4 (210X297 common eaves) -11- Printed by the Central Bureau of Standards of the Ministry of Economic Affairs A6 --- V. Description of the invention (1ϋ ) Inert bases such as gelatin and glycerin, or the active ingredients of sucrose and gum arabic; and mouthwashes containing the active ingredients of suitable liquid loam carriers. Recipes administered by the rectum falsely contain ingredients such as cocoa butter or salicylate A representative of a suitable base-based suppository. A formula suitable for vaginal administration is pseudo-denoted as a pessary, a tampon, an emulsion, a gel, a paste, a foam, or a spray formulation, which contains, for example, ddPN, in addition to the ddPN ingredient. Known carriers are suitable. Formulas suitable for non-gaming administration include water-soluble and water-insoluble. · Sterile injectable injections containing anti-gasification agents, buffers, and preparations Inoculants and solutes, The solute is an isotonic solution that is compatible with the blood dissolution of the skull; and a water-soluble and non-water-soluble sterile liquid suspension, which contains a suspension and thickening agent. The formula can be expressed in a single-dose or multiple-dose sealed container , Such as ampoules and vials, and can be stored in lyophilized conditions, only need to be added with sterile liquid carrier, such as water for injection before use. Quick injection and suspension can be prepared from the above-mentioned non-serum powder , Granules and tablets, etc. The preferred unit dose formulation contains a single daily dose or unit, a single daily small dose, or a suitable part of the ddPN ingredient and / or PNP inhibitor. The nucleoside chain acidification used in the present invention Enzyme (PNP) inhibitors are diverse compounds, of which JI: many are typically known in technology circles. Many •---—. — ______- These compounds are especially shown in the development of cancer chemotherapy >; In the chapter of Stoeckler, CRC is sold, 1984, title ★ Puridine Nucleoside Phosphorylation _: The goal of chemotherapy: pages 35-60 and the end (please read the notes on the back before filling this page) . Bae, booked • , A 4 (210X297 Gongji) -12- A6 B6 2 ^ 138- V. Description of the invention (11) Lai Medicine 11, No. 7, 1988 Λ 抦 昤 nucleoside phosphorylase (PNP) inhibitor: enhanced Selective immunosuppressive agents, Sircar and Gilbertsen, pages 653-668. See also U.S. Patent Application No. 704,991, edited February 25, 1985, corresponding to EP-A-193, 454; U.S. Patent Application Case No. 660, 152, abandoned on October 12, 1984 and U.S. Patent Application No. 767, 202, edited on August 22, 1985, corresponding to 4-178,178; U.S. Patent Application No. 593, No. 063, March 26, 1984_Edition and US Patent Application No. 698, 905, compiled on February 11, 1985, corresponding to the pressure? 4-156,559; U.S. Patent Application No. 547, 297, compiled on October 31, 1983 and U.S. Patent Application No. 657, 211, compiled on June 19, 1985, corresponding to EP-A-14 5, 207; and U.S. Patent Application No. 900, 486, June 26, 1986, and U.S. Patent Application No. 59,419, compiled on June 18, 1987, corresponding to EP-A- 260,491; all are described here with reference to the literature. This item is composed of many PNP inhibitors. The present invention is not limited and any PNP inhibitory compound can be used. The PNP inhibitory property of the PNP inhibitor is 1C ». Less than 5u is better. A special case of the present invention is to use 2 ', 3 · -didegastropine nucleosides, such as 2,3'_dideoxyinosine or 2', 3 · -didegastric nucleus Glycosides, combined with 9-substituted derivatives of guanosine, such as those shown in EP-A-178,178 (US Patent No. 4,772,286), EP-A-156,559, Drugs and Reactions 3/4 (1987) 253-256 pages and future medicines (please read the precautions on the back before writing this page) • Install · 'Order · Central Bureau of Economic Affairs printed armor 4 (210X297 public love) -13- 212138 A6 B6 V. Invention Description (12) Agent 11, 653 (1988), or a derivative of EP-A-260,491 9-substituted with 9-deacridine guanine purulant, such as the following formula
{請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局印焚* 其中為叫或SH; RT為氫或NH2 ; R»為氫或ΝΗι , η 為0至4之整數，及Ar為（i)苯基未經取代或取代有鹵素， 1至4磺原子之烷基，1至4硪原子之氫氣基，烷氣基，或 三Ε甲基，（ii)2·或3-噻盼基，或3-呋喃基；或 葯學可接受性鹽；及尤其該化合物其中R*為0H為η為1 者。 使用於合併ΡΝΡ抑制劑之例示說明例為：（a〉ForBycin B, (b)8-胺基鳥糞嗦昤，8-胺基鳥糞核苷，1-/3-D核糖 呋喃耱基-1H-1,2, 4-三唑-3-羧脒，8-胺基- 9-(1,3-二 羥基-2“丙氣甲基）鳥糞嗉昤，9-去吖鳥糞核苷，9-去吖 肌核苷，5’-去氣-5’-氛-9-去"丫肌核苷，5’-去氣-5’-碘-9-去吖肌核苷，及8-胺基-9-去吖- 9-(3-噻盼基甲基） 鳥糞嘌昤，及（c) 8-胺基-9-苄基鳥糞嗉昤，8-胺基-θα-噻盼基 甲基〉鳥糞嗦昤 ，及 8-胺基 -9-(3-噻吩基 甲基） 鳥糞嗦昤。此等實施例中（b)及（c)組之PNP抑制劑較佳。 最佳之PNP抑制劑偽（c)组者。 .装· '訂· •缘· 甲 4(21·0Χ297 公爱) 經濟部中央標準局印製 A6 g.12138_b6_ 五、發明説明（13) 特別適宜PNP抑制劑包括，不具限制，8-胺基鳥糞核 苷，8-胺基鳥糞嗦昤，及其9-苄基，9-(2-噻盼基甲基） 及9-(3-¾盼基甲基）類似物，及8-胺基-9-去吖島糞嗉昤 及其9-苄基，9-(2-噻盼基甲基）及9-(3-噻盼基甲基）類 似物。 有目的地抑制逆轉錄病毒感染寄主，尤其是人免疫缺 乏病毒感染寄主中之可用PNP,將之修整使2’，3· -二去 嘌昤核苷於感染細胞内具有足夠之抗逆轉錄病毒能力而 • . 不會對未感染細胞有任何顯著性傷害。 典型地本發明之PNP抑制剤僳以約0.5至150mg/kg/天 之量投予，.亦丐因方便而採以多分割式劑量。最有利地 型式係投予之PNP抑制劑劑量抑制可用PNP活性不超過約 98%。投予PNP抑制剤之劑量抑制可用PNP活性較好者約 50至98X,更好者約65至95X及有利者約75至95X。PNP抑 制劑之組成物以前述2’，3’-二去氣嘌昤核苷組成物之相 同方式調配或PNP抑制劑可與2’，3^-二去氣嗦昤核苷於 相同配方中併述第二活性成分。 兩種活性成分（ddPN與PNP抑制劑）可同時以相同或不 同途徑，以相同或不同地方投予，或可及時於分離點投 予而提供當2’，3’-二去氣嗦昤核苷存在時，具有有效PNP 控制性。完成此次投予活性剤分離範圍係決定於可用PNP 數量及PNP抑制劑自身降解速率。因此等原因，較佳劑量 為以分割式劑董每天2至4次，最佳者你同時投予2種劑。 (請先閑讀背面之注意事項再填寫本頁) -装· •訂. .綠· 甲 4(2·10Χ297 公簷) 15- 經濟部中央標準局印製 A6 Λ Β6 21^13® ----- 五、發明説明（14) 參考下列實施例，本發明將更為全盤了解，該實施例 傺作例示說明之用而非限制本發明。 審掄例1 : (a) 1Θ000膠囊製備： 2’，3’-二去氧腺核苷 60s 8-胺基-9-.(3-噻吩基甲基）鳥粪嗦昤 1400g 2種化合物一起混合及《充入適於投予之謬囊，例如大 人每8小時服用2個膠囊，每日3次。 相同製法為其它2’，3’-二去氧瞟昤核苷之配方，例如 二去氧肌核苷，合併與適宜之PNP抑制劑。 (b) 為10000掴膠囊： 2’，3’ -二去氣肌核苷 50g 胺基-9-去吖-9-(3-嚜盼基甲基）-鳥糞瞟昤（EP-A-260, 491之化合物9) 2000g (c) 為10βθθ傾膠囊： 2’，3’-二去氣肌核苷 50g 8-胺基-9-(2-噻吩基甲基）鳥糞嗦昤 1500g ir施例2 :藉pnp抑制劑增強二去氣核苷之抗逆轉錄病毒 活性可於細胞培養中渕定，舉例如下： 甲 4(210X297 公沒） -16- (請先閲讀背面之注意事項再填寫本頁) .裝. •訂· ，線. 21213® as ___B6 _ 五、發明説明（15) H9细胞〔Popovic;等人497 (1984)〕或 ATH8 細胞[Mitsuye 及 Broder，Proc· Natl. Acad. Sci· 美國1911 (1986)]以特殊二去氧嗦呤核苷（ddPN〉或 合併與PNP抑制劑之有效嗉昤核苷楼酸化梅（PNP)抑制量 來處理。然後細胞曝.薄於HIV病毒，培育數天後，依據實 驗原案其係由 Mitsuye 及 Broder，Proc. Natl* Acad· Sci·美國83, 1911 (1986)所—槪述而決定生存細胞數目 。細胞培養中的絕大多數生存細胞以經合併ddPN及PNP 抑制劑處理者與單獨使用ddPN者比較，顯示緒PNP抑制 劑ddPN於保護此等細胞免受HIV病寓細胞病理傷害之能 力增強。 (請先閑讀背面<*注意事項再填寫本頁) •打. •線. 經濟部中央標準局印製 甲 4(210X297 公簷)(Please read the precautions on the back before filling this page) Printed by the Central Bureau of Standards of the Ministry of Economic Affairs * Among them is called or SH; RT is hydrogen or NH2; R »is hydrogen or ΝΗι, η is an integer from 0 to 4, and Ar (I) phenyl is unsubstituted or substituted with halogen, an alkyl group of 1 to 4 sulfonic atoms, a hydrogen group of 1 to 4 atomic atoms, an alkyl group, or a tri-E methyl group, (ii) 2 · or 3- Thiapanyl, or 3-furyl; or a pharmaceutically acceptable salt; and especially the compound wherein R * is 0H and η is 1. Illustrative examples for the use of combined PNP inhibitors are: (a> ForBycin B, (b) 8-amino guano, 8-amino guanosine, 1- / 3-D ribofuranyl- 1H-1,2,4-triazole-3-carboxamidine, 8-amino-9- (1,3-dihydroxy-2 "propanolmethyl) guano 嗉 昤, 9-acridine guano nucleus Glycosides, 9-deazinosine, 5'-degassing 5'-atmosphere-9-de " ya myosin, 5'-degassing 5'-iodine-9-deazinosine, And 8-amino-9-deacridin-9- (3-thiapanylmethyl) guano purpura, and (c) 8-amino-9-benzyl guano pura, 8-amino- θα-Thipanylmethyl> Guano, and 8-amino-9- (3-thienylmethyl) Guano. The PNP inhibition of groups (b) and (c) in these examples The agent is the best. The best PNP inhibitor pseudo (c) group.. Installed · 'ordered' · margin · A 4 (21 · 0Χ297 public love) A6 g.12138_b6_ printed by the Central Standards Bureau of the Ministry of Economic Affairs (13) Particularly suitable PNP inhibitors include, without limitation, 8-aminoguanosine, 8-aminoguanosine, and its 9-benzyl, 9- (2-thienylmethyl) and 9- (3-¾-panylmethyl) analogues, and 8-amino-9-deacid-free excrement Its 9-benzyl, 9- (2-thienylmethyl) and 9- (3-thienylmethyl) analogs. Purposely inhibits retroviral infection hosts, especially human immunodeficiency virus infection hosts Among them, PNP can be used, and it can be trimmed to make 2 ', 3 · -didepurinium nucleoside have sufficient anti-retroviral ability in infected cells. • It will not cause any significant damage to uninfected cells. Typically The PNP inhibitory compound of the present invention is administered in an amount of about 0.5 to 150 mg / kg / day. The multi-split dosage is also used for convenience. The most advantageous type is the dosage of the PNP inhibitor administered to inhibit available PNP activity Not more than about 98%. The dose of PNP inhibitor can be used to inhibit the PNP activity of the better about 50 to 98X, better about 65 to 95X and favorable about 75 to 95X. The composition of the PNP inhibitor is 2 ' , 3'-didegastropine nucleoside composition can be formulated in the same way or PNP inhibitor can be combined with 2 ', 3 ^ -didegastropine nucleoside in the same formula and the second active ingredient is described. Ingredients (ddPN and PNP inhibitors) can be administered in the same or different routes and in the same or different places at the same time, or can be timely The separation point is administered to provide effective PNP control when 2 ', 3'-didegastropine nucleosides are present. The separation range of the active activity for the completion of this administration depends on the number of available PNPs and the degradation of the PNP inhibitor itself Rate. Therefore, for other reasons, the preferred dosage is divided into two or four times a day, the best you are to administer two kinds of agents at the same time. (Please read the precautions on the back before filling this page)-Pack · • Order ... Green · A 4 (2 · 10Χ297 common eaves) 15- Printed by the Central Bureau of Standards of the Ministry of Economic Affairs A6 Λ Β6 21 ^ 13® ----- V. Description of the invention (14) With reference to the following examples, the present invention will For a more complete understanding, this embodiment is for illustrative purposes and not for limiting the present invention. Examination Example 1: (a) Preparation of 1Θ000 capsules: 2 ', 3'-dideoxyadenosine 60s 8-amino-9-. (3-thienylmethyl) Guano 1400g 2 compounds together Mix and "fill into the fallacies suitable for administration, for example, adults take 2 capsules every 8 hours, 3 times a day." The same preparation method is the formulation of other 2 ', 3'-dideoxyl nucleoside, such as dideoxyinosine, combined with a suitable PNP inhibitor. (b) 10000 slap capsules: 2 ', 3'-didegasin 50g, amino-9-desa-9- (3-triamylmethyl) -guano feces (EP-A- Compounds 260, 491 9) 2000g (c) 10βθθ tilt capsules: 2 ', 3'-dideoxyinosine 50g 8-amino-9- (2-thienylmethyl) Guano 1500g ir Example 2: Enhancing the antiretroviral activity of dideoxyribonucleoside by pnp inhibitor can be determined in cell culture, for example: A 4 (210X297 public) -16- (please read the precautions on the back first (Fill in this page). Packing. • Order., Line. 21213® as ___B6 _ 5. Description of the invention (15) H9 cells [Popovic; et al. 497 (1984)] or ATH8 cells [Mitsuye and Broder, Proc · Natl. Acad Sci. United States 1911 (1986)] treated with special dideoxynucleoside (ddPN) or an effective amount of PNP inhibitor combined with PNP inhibitor. Then the cells were exposed. Thin HIV virus, after several days of incubation, according to the original experiment, it was determined by Mitsuye and Broder, Proc. Natl * Acad. Sci. US 83, 1911 (1986)-the number of living cells was determined. The vast majority of cell culture Health The stored cells were compared with those treated with ddPN and PNP inhibitors compared with those who used ddPN alone, showing that the ability of PNP inhibitor ddPN to protect these cells from HIV disease and cell pathological damage is enhanced. (Please read the back side first < * Notes to fill out this page) • hit. • line. The Central Bureau of Standards of the Ministry of Economic Affairs printed a 4 (210X297 eaves)